title: Novel PEGylated basal insulin LY2605541 has a preferential hepatic effect on glucose metabolism.
abstract: The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg(-1) ⋅ h(-1) [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg(-1) ⋅ h(-1)]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg(-1) ⋅ min(-1) within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg(-1) ⋅ min(-1) in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (-0.01 ± 0.13), and LY0.5 (-0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Mary Courtney
authors.initials: MC
authors.lastname: Moore
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.forename: Vikram P
authors.initials: VP
authors.lastname: Sinha
authors.forename: John M
authors.initials: JM
authors.lastname: Beals
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Jacober
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D061268:Insulin Lispro / Q000494:pharmacology*; D061385:Insulins / Q000494:pharmacology*; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D061268:Insulin Lispro; D061385:Insulins; C587357:LY2605541; D019344:Lactic Acid; D011092:Polyethylene Glycols; D005947:Glucose